In general, a drug such as an anti-cancer drug, which is administered orally or by injection, does not have the effect specific to the target lesion, and therefore, can not sufficiently exhibit the effect even if it is a potent drug, and besides, affects the normal organs and tissues other than the lesions with severe side effects. Dosage of such a potent drug is suppressed to increase due to its possibility to cause a side effect. This is the reason why the system for a lesion-oriented drug, called a drug delivery system (DDS), is continuously and competitively researched and developed worldwide. The DDS research is important especially in the field of anti-cancer drugs which have potential to bring about many side effects.
Focusing on the fact that an anti-tumor drug can be polymerized to become a lesion-oriented and sustained-release type agent, the present inventors found earlier a unique phenomenon that a polymeric agent having a molecular weight of 40 kda or more accumulates selectively in the tumor tissues and is retained there for a longer period of time, and then designated this phenomenon as an EPR (enhanced permeability and retention) effect (non-patent document 1). This phenomenon is observed in polymeric agents and lipid micro-particles and the like.
Up to now, based on such observations the inventors produced many polymeric agents obtained by reacting drugs with various polymers. It was found that these polymeric agents exhibited a high rate of accumulation in tumors and inflammed lesions via the EPR effect described above, and that as the result, they became superior polymeric anti-tumor agents which were excellent in anti-tumor effect and had few side effects on normal organs as compared to low molecular weight anti-tumor drugs (Patent document 1, Patent document 2, Patent document 3 and Non-patent document 2).
Among these polymeric anti-tumor agents, the polymeric anti-tumor agent described in Patent document 3, which has a polymeric micelle complex structure formed by associating a low molecular weight anti-tumor drug with a styrene-maleic acid co-polymer (SMA) via non-covalent bonding (hereinafter designated as SMA micelle complex), has been found to be a superior anti-tumor agent that has an especially superior anti-tumor effect and also had few side effects on normal organs.    Patent document 1: Japanese Patent Publication (Kokai) No. 11-60499    Patent document 2: Japanese Patent Publication (Kokai) No. 2003-73273    Patent document 3: WO 2004/103409 A1    Non-patent document 1: Cancer Res., 44, 2115-2121, 1984; ibid, 46, 6387-92, 1986; Anticancer Res., 13, 1287-1292, 1993    Non-patent document 2: J. Controll. Release, 74, 47-61, 2001; Adv. Enzyme Regul., 41, 189-207, 2001    Non-patent document 3: Cancer Res., 63, 3567-3574, 2003    Non-patent document 4: Bioconj. Chem. 13, 1031-1038, 2002